This invention relates to the use of the carbocyclic analogue of 2'-deoxyguanosine (2'CdG) in the prophylaxis and treatment of infections by viruses including herpes simplex virus types I and II, cytomegalovirus, and hepatitis B virus.
Among the many kinds of viruses that infect man, two types are especially important with regard to their ubiquity, clinical significance and economic impact: the herpes viruses and the hepatitis viruses.
The six human herpesviruses, herpes simplex virus types 1 and 2 (HSV-1, HSV-2), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpes virus 6 (HHV 6), are widely disseminated in the population and are responsible for a broad spectrum of human diseases, ranging from minor annoyances such as cold sores to highly destructive infections of the central nervous system (encephalitis), and potentially fatal neonatal infections. Once infected, an individual may suffer lesions and recover, but the virus usually persists for the life of the individual in a state of latency in nerve or other cells and may periodically become reactivated to cause recurrent clinical lesions or other disease states. In addition, it has been long recognized that herpesvirus infections are considerably more severe in certain immunosuppressed patients, particularly those with depressed cell-mediated immunity such as cancer patients and organ transplant recipients, individuals with hereditary immune deficiencies, as well as individuals with acquired immune deficiency syndrome (AIDS).
HSV-1 and HSV-2 manifest themselves in a number of clinical diseases, including infections of the central nervous system (encephalitis), skin, lips, and the genitalia. Oral herpes is caused generally by HSV-1 and genital herpes by HSV-2, but both viruses can cause either infection (and each can cause encephalitis). The estimated annual number of episodes of recurrent herpes labialis is over 100 million in the United States alone. It also has been estimated that over 1,000,000 new clinically reported cases of genital herpes occur each year in the United States, and that currently as many as 60 million cases per year of recurrent genital herpes may exist. In addition, a large number of individuals will excrete virus in the absence of clinical symptoms and thus constitute a silent but persistent reservoir for transmission of virus through sexual contacts.
Human cytomegalovirus (CMV) infections are among the most common cause of congenital (human intrauterine and perinatal) infection in the world today, and represent a frequent and serious complication in immunosupressed inividuals. Congential CMV infections are associated with retinitis, hearing loss, birth defects, mental retardation, and death. In immunosuppressed adults, CMV is associated with serious infections of the eye such as chorioretinitis, as well as infections of other organs, including hepatitis, esophagitis, gastritis, pneumonitis and encephalitis.
Hepatitis B virus (HBV) is the most prevalent of the highly contagious hepatitis viruses, infecting an estimated 200 million people worldwide. HBV is a major cause of acute and chronic hepatitis, cirrhosis, and primary hepatocellular carcinoma. Of the estimated 200,000-250,000 people in the United States who are infected annually, more than 100,000 require hospitalization and approximately 250 die of active disease each year. Between 6% and 10% of infected individuals become carriers of the virus. Approximately 25% of these carriers will develop cirrhosis and approximately 1% will develop hepatocellular carcinoma.
Other than exclusion of virus-host contact, there are two types of defenses against viral infection: vaccination and chemotherapy. Vaccination has had some success in preventing or limiting certain viral infections. However, there are certain limitations associated with the use of vaccines. First, vaccination, with rare exception, is a prophylactic measure which is useful only prior to the onset of the disease. Second, factors such as the age of the individual, the presence of preexisting antibody, either passively acquired maternal antibody or antibody secondary to natural infection, and the site of injection may influence the effectiveness of some vaccines. In addition, vaccination involves the introduction into the body of material which can, in some instances, pose risks which result in adverse reactions in the individual.
A number of nucleoside analogs have been proposed for chemotherapeutic treatment of viruses such as HSV, HBV and CMV. U.S. Pat. No. 4,396,623 (Shealy et al.) refers to the use of certain carbocyclic analogs or uracil nucleosides for the treatment of various human and animal diseases caused by DNA viruses, such as Herpes simplex virus. U.S. Pat. No. 4,177,348 (Shealy et al.) and U.S. Pat. No. 4,232,154 (Shealy et al.) refer to carbocyclic analogues of cytosine nucleosides and their activity against DNA viruses, such as herpes simplex virus Type 1. U.S. Pat. No. 4,543,255 (Shealy et al.) and U.S. Pat. No. 4,728,736 (Shealy et al.) refer to carbocyclic analogues of purine 2'-deoxyribofuranosides and ribofuranosides, respectively, and their activity against DNA viruses, exemplified by herpes simplex virus Type 1 and Type 2.
Of the nucleoside analogs available, acyclovir (acyloguanosine) is the agent currently indicated for the topical, oral or intravenous therapy of a number of clinical manifestations of HSV-1 and HSV-2 as it is a potent inhibitor of HSV replication. However, a number of toxic effects have been reported. Topical application of acyclovir can cause transient stinging, keratitis, follicular conjunctivitis and allergies when used to treat herpetic keratitis. Infusion may produce nephrotoxicity in patients receiving large doses due to deposition of drug crystals in renal tubules. Other toxic effects have been attributed to the high pH (alkalinity) required to keep acyclovir in solution. Furthermore, while the antiviral activity of acyclovir has been ascribed to its ability to be incorporated into the viral DNA, acyclovir induced-DNA chain incorporation and termination of cellular genes may lead to additional forms of toxicity, including chromosomal damage.
Acyclovir has also been used against HBV although its use is disadvantaged by the same potential side effects described above. In addition, while it is effective during short term administration in reducing markers associated with HBV replication, such as plasma levels of HBV DNA polymerase, cessation of drug administration may result in the return to pretreatment level of virus replication.
Other drugs currently used to treat HBV include adenosine arabinoside (ara-A) and adenine arabinoside monophosphate (ara-AMP, a form of the drug which allows it to be administered intramuscularly). These drugs are effective alone or in combination in decreasing levels of circulating HBV DNA polymerase activity in patients infected with HBV. However, complete inhibition of HBV may not result from these treatments, as DNA polymerase activity has been demonstrated to increase following cessation of drug therapy. Furthermore, both ara-A and ara-AMP are also associated with substantial toxicity. Untoward effects of these drugs commonly experienced by patients include nausea, anorexia, fatigue, diarrhea, vomiting, and reversible bone marrow suppression with thrombocytopenia. In addition, a peculiar neuromuscular pain syndrome that produces pain and cramping, most pronounced at the site of injection, and which may last for months following cessation of drug administration has been described. Payne, John A. "Chronic Hepatitis: Pathogenesis and Treatment," Disease a Month, March, pp. 117-59 (1988).
Acyclovir has also been used for prophylaxis of CMV, but has been reported to be ineffective against established systemic CMV infections as well as against CMV retinitis. Broad spectrum antibiotics, corticosteroids, and antifungal agents have also been reported to be without therapeutic benefit against this disease. An antiviral agent, ganciclovir (dihydroxy propoxymethyl guanine) (DHPG) an acyclic nucleoside, has been reported to be effective against CMV retinitis but is of limited potency and is associated with dose-limiting toxicity. Its activity is described in Declercq et al., Antiviral Research Vol. 3, 17-24 (1983) and Vol. 4, 119-133 (1984).
The carbocyclic analogue of 2'-deoxyguanosine(.+-.)-2-amino-1,9-dihydro-[(1.alpha.,3.beta.,4.alpha.)-3 -hydroxy-4(hydroxymethyl)cyclopentyl]-6H-purin-6-one] (2'-CdG) has been reported to have in vitro antiviral activity against HSV-1 and HSV-2 (Shealy et al., J. Med. Chem. 27:1416, 1987), human cytomegalovirus (Shannon et al., in Advances in Chemotherapy of AIDS, Diasio et al., eds., Pergamon Press, Inc., New York pp.75-95, 1990, as well as CMV (WO91/13549, 1991)), and human hepatitis-B virus (Price et al., Proc. Natl. Acad. Sci. USA 86:8541, 1989). In addition, it has also shown in vivo antiviral activity against HSV-1 and HSV-2 (Shannon et al., in Proceedings of the American Society of Virology, Annual Meeting, 1985).